Method of opening reservoir of containment device

ABSTRACT

A method is provided for selectively opening a containment reservoir. The method includes providing a device which comprises a substrate in which at least one reservoir is located and covered by a reservoir cap; and directing laser light to said reservoir cap to cause the reservoir cap to disintegrate or become permeable. The device may be an implantable medical device. The reservoirs may contain a drug for controlled release or a biosensor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 11/291,973,filed Dec. 1, 2005, now pending, which is a continuation of U.S. patentapplication Ser. No. 10/042,996, filed Jan. 9, 2002, now U.S. Pat. No.6,976,982, which claims benefit of U.S. Provisional Application No.60/260,725, filed Jan. 9, 2001. These applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The present invention is generally in the field of implantable microchipdevices and methods for use thereof, particularly in ophthalmic andother medical applications.

The relatively small size, rounded shape, and location of the eye havemade the development of new methods and devices for drug delivery to theeye difficult. The most common method of drug delivery to the eye is byliquid eye drops. This method of drug delivery is limited to those drugsthat can diffuse through the eye tissue (i.e. typically low molecularweight drugs) and those drugs that can be formulated as a liquid or gel.

Alternative delivery methods include the implantation of drug deliverydevices inside of the eye. For example, U.S. Pat. No. 6,063,116 toKelleher discloses an intraocular polymeric implant for sustainedrelease of a cell proliferation-modulating agent. As another example,Ambati, et al, “Transscleral Delivery of Antibodies to the PosteriorSegment” Investigative Ophthalm. & Visual Sci., 40(4): 457-B417 (Mar.15, 1999) discloses implanting osmotic pumps containing FITC-IgG on thescleral surface or beneath a lamellar scleral flap for targeted deliveryto the choroid and retina.

These implants may allow larger molecular weight drugs to be delivered(depending on the presence of diffusion limitations based on the depthof the target tissue layer), but they typically only have the ability topassively release a single drug.

PCT WO 00/40089 discloses a method for delivering a therapeutic ordiagnostic agent to the retina and choroid by contacting the sclera withthe agent and using an implant device for enhancing transport of theagent through the sclera. The reference mentions that the implant can bea microchip comprising reservoirs containing the desired agent. It wouldbe advantageous to develop new and improved systems using microchipdevices, as described in U.S. Pat. No. 5,797,898, U.S. Pat. No.6,123,861, PCT WO 01/64344, PCT WO 01/35928, and PCT WO 01/12157, forthe controlled delivery of drugs and the controlled exposure of sensorsin ophthalmic and other medical applications wherein implantationpresents challenges such as described above for the eye. It also wouldbe desirable to provide devices and methods of use thereof for deliveryand sensing at locations in patients where implantation is desirable insmall spaces, particularly those involving curved or rounded tissuesurfaces.

SUMMARY OF THE INVENTION

Microchip device arrays that can conform to a curved surface areprovided for the controlled release or exposure of reservoir contents.The arrays comprise two or more microchip device elements, each of whichincludes a plurality of reservoirs that contain molecules for controlledrelease or components for selective exposure, and a means for flexiblyconnecting the device elements.

Preferably, the means for flexibly connecting comprises a flexiblesupporting layer attached to a surface of the device elements. Theflexible supporting layer can, for example, comprise a polymer, such asa polyimide, polyester, parylene, or hydrogel. The flexible supportinglayer typically is attached the microchip device elements on the sidedistal the release/exposure opening of the reservoirs (i.e. the releaseside). Additionally or alternatively, the flexible supporting layer canbe secured to the release side if the flexible supporting layer isprovided with one or more apertures aligned the reservoir openings or ifthe flexible supporting layer is porous or permeable to (i) moleculesreleasable from the reservoirs or (ii) environmental molecules ofinterest that would need to contact the reservoir contents).Alternatively, the microchip device elements could be effectivelyimbedded within the flexible supporting layer.

In other embodiments, the means for flexibly connecting comprises one ormore hinges or flexible tethers connecting two or more of the deviceelements.

In preferred embodiments, the microchip device array is suitable forimplantation onto or into a patient, wherein the array can conform tothe curvature of a tissue surface. In one embodiment, the array isimplanted into or onto the eye of the patient, wherein the tissuesurface comprises ophthalmic tissue.

In several embodiments, the reservoirs of the device elements containdrug molecules for release. In other embodiments, the reservoirs containone or more secondary devices, such as a sensor, for exposure. A singlearray or a single device element can include both drugs for release andsensors. Such an array could be automated to release a particular dosageof drug in response to a condition or change measured by the sensors.The reservoirs also can contain diagnostic reagents, catalysts,combinatorial chemistry precursors, and fragrance molecules.

The microchip device array may comprise reservoir caps over thereservoirs, and optionally can include means for a user to wirelesslycommunicate with the microchip device elements. Such communicating meanscan comprise a photocell to receive incident light energy, such as froma laser source.

Microchip device array having active microchip device elements cancomprise an energy storage means, such as a capacitor, a battery, orboth. Optionally, the array includes electrical connections between twoor more of the microchip device elements, such that the microchip deviceelements can be powered or controlled by a common energy source orcontrol source, respectively.

Methods are provided for delivering drug molecules to a patientcomprising implanting into or onto a tissue surface of the patient themicrochip device array which contains drug, and selectively releasingfrom one or more of the reservoirs an effective amount of the drugmolecules. In one embodiment, the microchip device array is implantedonto or into the sclera or another surface of the eye of the patient.The release of drug can be activated wirelessly, such as by applicationof light to the microchip device array. For example, an ophthalmic lasercould be used. The laser light could, in one method, remove or permeateone or more reservoir caps which cover the reservoirs. Other suitabletissue surfaces include, but are not limited to, the stratum corneum orother skin tissues, mucosal membranes, blood vessels, bone, brain, andbladder.

In another method, molecules or a physical property is sensed at a site,wherein the method comprises implanting at a site the microchip devicearray which contains sensors, and selectively exposing at least onesensor of the sensors to molecules or a property at said site, therebypermitting said at least one sensor to sense said molecules or property.The sensor, for example, could comprise a pressure sensor or a chemicalsensor.

More general methods are also provided for ophthalmic sensing.

Microchip devices have the advantage of small size, variable shape, andthe ability to actively or passively control release or exposure of thecontents of its reservoirs. The microchip devices can contain multipledrugs or chemicals, can contain sensors or diagnostic reagents, and canbe controlled using microprocessors, remote control (i.e. telemetry), orbiosensors. Additionally, the microchip devices for chemical deliveryand selective exposure can be used with known ophthalmic technology(such as ophthalmic light sources, such as lasers or other focusedlight) to provide a source of power or data transmission, or as a meansfor opening reservoirs in the microchip devices, for example bytriggering reservoir cap disintegration. The microchips can provideaccurate and controlled local delivery of drugs, advantageously reducingor avoiding systemic release.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C illustrate how an array of flat, rigid microchips areincorporated onto a flexible supporting layer containing electronicconnections and shared power and control sources.

FIG. 2A illustrates one embodiment of a configuration of an ophthalmicmicrochip device for drug release into the eye that is equipped forpower and data transmittal by laser.

FIG. 2B illustrates a process of using an ophthalmic laser to transmitpower and data to such an ophthalmic microchip device implanted in theeye.

FIG. 3 illustrates one embodiment of a configuration of a microchipdevice for drug release having a plurality of discrete reservoir capscovering openings in the reservoirs.

DETAILED DESCRIPTION OF THE INVENTION

The eye is a relatively small organ. Both the inside and outsidesurfaces of the eye are curved, so the size, shape, and rigidity of anydevice used to deliver drugs to the eye or used as a sensor in the eyeis therefore important. Microchip devices can be made large or small,depending on the specific requirements of the particular application.The substrates for these microchips can be composed of semiconductors orother material that protects the contents of the reservoirs until it isdesired to release them or expose them to the surrounding environment.For small devices, the shape and rigidity of the substrate material isnot as important as it is for larger devices. Some typically rigidsubstrate materials (e.g., silicon) can be made flexible, for example,if they are made thin enough. However, as a flat, rigid microchip isenlarged or made thicker, it is less able to conform to the curvature ofthe eye. This can be a problem if it is necessary for the entire surfaceof the device to contact the surface of the eye, another curved tissuesurface, or any other curved surface for that matter.

Therefore, microchip device arrays which can conform to curved surfaces,that is, flexible microchip devices, have been developed. In a preferredembodiment, this is accomplished with a microchip device that is made upof an array of several small microchip device elements that are attachedto a flexible supporting layer. Each microchip on the supporting layermay be independently controlled (i.e. individual power and controlsources) or the array of microchips may be controlled as one unit (i.e.shared power and control sources) through electrical connections builtinto the flexible supporting layer (see FIG. 1).

In preferred embodiments, the devices are adapted for use in deliveringdrugs or other chemicals to the eye, sensing changes in the eye orconducting other diagnostic tests, and combinations thereof, using, forexample, a device array composed of rigid microchips which conforms to acurved surface of either the interior or exterior of the eye. Certaineye conditions, notably macular degeneration and diabetic retinopathy,can be treated with periodic administration of medication delivered tothe eye; however, the means for doing so, such as injections, aredifficult. An implanted microchip device, such as described herein,should provide an improved means for delivering doses of one or moretypes of medication to the eye on a periodic basis for an extendedperiod of time. The microchips can provide accurate and controlled localdelivery of drugs, advantageously reducing or avoiding systemic release.

The Devices

In preferred embodiments, the device comprises microchip device elementsthat are attached to or integral with a flexible supporting layer.Preferably, an array of at least two (e.g., at least four, at leastfive, at least twelve, etc.), microchip device elements forms a single,larger flexible device that can conform to the curvature of tissuesurfaces, such as on surfaces of the eye, as detailed below.

In other embodiments, flexible microchip devices are provided in theform of a single microchip device element, or an array of two or moremicrochip device elements, having a flexible substrate. Such embodimentscould be provided, for example, by molding or otherwise formingappropriate polymeric substrates, and would be particularly suitable forpassive release designs.

The Microchip Device Elements

The microchip device (i.e. the microchip device elements) is describedin U.S. Pat. No. 5,797,898 and No. 6,123,861, both to Santini, et al.,and PCT WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157, whichare hereby incorporated by reference in their entirety. Each microchipdevice includes a substrate having a plurality of reservoirs containingreservoir contents for release or exposure.

The molecules to be delivered may be inserted into the reservoirs intheir pure form, as a liquid solution or gel, or they may beencapsulated within or by a release system. As used herein, “releasesystem” includes both the situation where the molecules are in pureform, as either a solid or liquid, or are in a matrix formed ofdegradable material or a material which releases incorporated moleculesby diffusion out of or disintegration of the matrix. The molecules canbe sometimes contained in a release system because the degradation,dissolution or diffusion properties of the release system provide amethod for controlling the release rate of the molecules. The moleculescan be homogeneously or heterogeneously distributed within the releasesystem. Selection of the release system is dependent on the desired rateof release of the molecules. Both non-degradable and degradable releasesystems can be used for delivery of molecules. Suitable release systemsinclude polymers and polymeric matrices, non-polymeric matrices, orinorganic and organic excipients and diluents such as, but not limitedto, calcium carbonate and sugar. Release systems may be natural orsynthetic, although synthetic release systems are preferred due to thebetter characterization of release profiles. The release system isselected based on the period over which release is desired, generally inthe range of at least three to twelve months for in vivo applications.In contrast, release times as short as a few seconds may be desirablefor some in vitro applications. In some cases, continuous (constant)release from a reservoir may be most useful. In other cases, a pulse(bulk) release from a reservoir may provide more effective results. Asingle pulse from one reservoir can be transformed into pulsatilerelease by using multiple reservoirs. It is also possible to incorporateseveral layers of a release system and other materials into a singlereservoir to achieve pulsatile delivery from a single reservoir.Continuous release can be achieved by incorporating a release systemthat degrades, dissolves, or allows diffusion of molecules through itover an extended period of time. In addition, continuous release can besimulated by releasing several pulses of molecules in quick succession.

The release system material can be selected so that molecules of variousmolecular weights are released from a reservoir by diffusion out orthrough the material or degradation of the material. Biodegradablepolymers, bioerodible hydrogels, and protein delivery systems arepreferred for release of molecules by diffusion, degradation, ordissolution. In general, these materials degrade or dissolve either byenzymatic hydrolysis or exposure to water in vivo or in vitro, or bysurface or bulk erosion. Representative synthetic, biodegradablepolymers include: poly(amides) such as poly(amino acids) andpoly(peptides); poly(esters) such as poly(lactic acid), poly(glycolicacid), poly(lactic-co-glycolic acid), and poly(caprolactone);poly(anhydrides); poly(orthoesters); poly(carbonates); and chemicalderivatives thereof (substitutions, additions of chemical groups, forexample, alkyl, alkylene, hydroxylations, oxidations, and othermodifications routinely made by those skilled in the art), copolymersand mixtures thereof. Representative synthetic, non-degradable polymersinclude: poly(ethers) such as poly(ethylene oxide), poly(ethyleneglycol), and poly(tetramethylene oxide); vinyl polymers—poly(acrylates)and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethylmethacrylate, acrylic and methacrylic acids, and others such aspoly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate);poly(urethanes); cellulose and its derivatives such as alkyl,hydroxyalkyl, ethers, esters, nitrocellulose, and various celluloseacetates; poly(siloxanes); and any chemical derivatives thereof(substitutions, additions of chemical groups, for example, alkyl,alkylene, hydroxylations, oxidations, and other modifications routinelymade by those skilled in the art), copolymers and mixtures thereof.

Each reservoir can contain a different molecule and dosage. Similarly,the release kinetics of the molecule in each reservoir can be varied bythe choice of the release system and cap materials. In addition, themixing or layering of release system and cap materials in each reservoircan be used to tailor the release kinetics to the needs of a particularapplication.

The distribution over the microchip of reservoirs filled with therelease system containing the molecules to be delivered can varydepending on the medical needs of the patient or other requirements ofthe system. For applications in drug delivery, for example, the drugs ineach of the rows can differ from each other. One row may contain ahormone and another row may contain a metabolite. In addition, therelease system can differ within each row to release a drug at a highrate from one reservoir and a slow rate from another reservoir.

FIG. 3 illustrates an embodiment of a microchip device 150, wherein themicrochip device 150 includes a substrate 160 having a plurality ofdiscrete reservoirs 162. A release system 166 including molecules fordelivery is located in the reservoirs 162, and each of the reservoirs162 has a discrete reservoir cap 168 positioned on the reservoir 162over the release system 166. Release or exposure of the release system166 is controlled by diffusion through or disintegration of thereservoir cap 168.

The reservoir cap can be an anode, such that upon application of anelectric potential between a cathode and the anode the reservoir cap isoxidized to facilitate its disintegration, thereby exposing thereservoir contents to a surrounding fluid. In another embodiment, thereservoir cap includes an electrically- or thermally-responsive polymerwhose integrity or porosity can be modulated (i.e. increased ordecreased) upon application of electrical energy to the reservoir cap(e.g., for the electrically responsive polymer) or to a nearby resistoror resistive heater (e.g., for the thermally responsive polymer).Similarly, the reservoir cap can include or be formed of a polymerhaving a porosity that can be modulated by application ofelectromagnetic energy, acoustic energy, or a particular chemicalspecies (e.g., for chemical actuation) provided by the microchip deviceor other source.

In the passive timed release drug delivery devices, the reservoir capsare formed from a material that degrades or dissolves over time, or doesnot degrade or dissolve but is permeable to the molecules to bedelivered. These materials are preferably polymeric materials. Materialscan be selected for use as reservoir caps to give a variety ofdegradation rates or dissolution rates or permeabilities to enable therelease of molecules from different reservoirs at different times and,in some cases, different rates. To obtain different release times(amounts of release time delay), caps can be formed of differentpolymers, the same polymer with different degrees of crosslinking, or aUV polymerizable polymer. In the latter case, varying the exposure ofthis polymer to UV light results in varying degrees of crosslinking andgives the cap material different diffusion properties or degradation ordissolution rates. Another way to obtain different release times is byusing one polymer, but varying the thickness of that polymer. Thickerfilms of some polymers result in delayed release time. Any combinationof polymer, degree of crosslinking, or polymer thickness can be modifiedto obtain a specific release time or rate. In one embodiment, therelease system containing the molecules to be delivered is covered by adegradable cap material which is nearly impermeable to the molecules.The time of release of the molecules from the reservoir will be limitedby the time necessary for the cap material to degrade or dissolve. Inanother embodiment, the cap material is non-degradable and is permeableto the molecules to be delivered. The physical properties of thematerial used, its degree of crosslinking, and its thickness willdetermine the time necessary for the molecules to diffuse through thecap material. If diffusion out of the release system is limiting, thecap material delays the onset of release. If diffusion through the capmaterial is limiting, the cap material determines the release rate ofthe molecules in addition to delaying the onset of release.

The microchip devices can be made and assembled using microfabricationmethods known in the art, particularly those methods described andreferenced in U.S. Pat. Nos. 5,797,898 and 6,123,861, both to Santini,et al., and in PCT WO 01/64344, WO 01/41736, WO 01/35928, and WO01/12157. These publications are hereby incorporated by reference.

The device is preferably constructed of and/or coated with, materialsknown in the art to be physiologically acceptable for long-termimplantation or contact with the ocular tissues.

Means for Flexibly Connecting

Preferably, the means for flexibly connecting comprises a flexiblesupporting layer secured to at least one surface of each of the deviceelements.

The flexible supporting layer typically is attached to the microchipdevice elements on the side distal the release/exposure opening of thereservoirs (i.e. the release side). Additionally or alternatively, theflexible supporting layer can be secured to the release side if theflexible supporting layer is provided with one or more apertures alignedto the reservoir openings or if the flexible supporting layer is porousor permeable to (i) molecules releasable from the reservoirs or (ii)environmental molecules of interest that would need to contact thereservoir contents. Alternatively, the microchip device elementseffectively could be imbedded within the flexible supporting layer.

The flexible supporting layer can be made of essentially any flexiblematerial, but preferably comprises a polymer. Representative examples ofsuitable polymers include polyimide, polyester, parylene, and hydrogels.Other flexible materials that are especially biocompatible includepolyethylene, polypropylene and silicone.

The flexible supporting layer also could be a laminate structure. Forexample, it could be comprised of an inner flexible material containingelectrical conductors that is coated with one or more biocompatiblematerials.

The microchip device elements, as well as other components, can besurface mounted onto or imbedded into the flexible supporting layer. Forexample, the microchip device elements and other components can besurface mounted using conductive adhesives, non-conducting adhesives(e.g., an epoxy), soldering, or wirebonding. Alternatively, themicrochip elements could be mechanically attached, for example by screwsor clips.

The flexible layer also may consist of or comprise a mesh material,which would generally be easier to suture to tissue. Such a meshmaterial could be biodegradable or non-biodegradable, depending upon theapplication.

In one embodiment, electrical connections or traces are built into themeans for flexibly connecting the device elements. For example, theincorporation of electrical connections into flexible polymer films iswell known by those skilled in the art of microelectronics packaging.Typical approaches include single and multiple layer flexible printedcircuits, and Multichip Modules-Deposited (MCM-D) using organic (usuallypolyimide) dielectric layers. For example, in the “chips first” style ofMCM-D, thinned chips are placed on a bottom dielectric layer and theninterconnected layers are built up over them, thereby embedding thechips. Other chips, e.g., the microchip device elements can then besurface mounted. Flexible circuit and MCM-D fabrication techniques aredescribed, for example, in Coombs, Printed Circuits Handbook, 4^(th) ed.(McGraw-Hill 1996) and Harper, Electronic Packaging and InterconnectionHandbook, 3^(rd) ed. (McGraw-Hill 2000).

It is also understood that small, rigid, passive-release microchips alsocan be incorporated onto a supporting layer so that they can betterconform to the curvature of the eye. Unlike the active microchips, thepassive microchips do not require any power or control sources orelectrical connections in the flexible substrate. In this case, theflexible substrate serves only to hold the passive microchip deviceelements in place.

In other embodiments, the means for flexibly connecting comprises one ormore hinges or flexible tethers connecting two or more of the deviceelements, so that the array can conform to the curved surface. Forexample, each of the four edges of a square microchip device elementcould be connected by one or more hinges or flexible tethers to the edgeof an adjacent microchip device element. The hinges or tethers could beconnected at the corners or along the edges of the device elements. Aflexible supporting layer could be used to form such tethers or hinges,or to complement them.

Contents of the Microchip Reservoirs

The microchip reservoir contents can be essentially any chemical or asecondary device, or portion thereof, that can be contained in areservoir of the microchip device. The term “secondary device” typicallyrefers to structures and does not include drugs or other chemicalmolecules that are intended to be released from the reservoirs. Themicrochip devices can contain multiple drugs or chemicals in a varietyof forms (e.g., solid, liquid, or gel) and can contain sensors ordiagnostic reagents.

In a preferred embodiment, the chemical is a therapeutic, prophylactic,or diagnostic agent. The term “drug” refers to any of these agents,unless a particular one is explicitly indicated, Representative types ofsuitable drugs include proteins, purified polypeptides and nucleic acidmolecules, as well as synthetic and natural organic molecules.

Representative examples of suitable therapeutic or prophylacticmolecules include antibiotics (e.g., tetracycline, chlortetracycline,bacitracin, neomycin, gentamicin, erythromycin, and penicillin);antibacterials such as sulfonamides, sulfadiazine, sulfacetamide,sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate;antivirals (e.g., idoxuridine, trifluorothymidine, acyclovir,gancyclovir and interferon); other anti-microbial drugs such asiodine-based preparation (e.g., triclosan, chlorhexidine);anti-allergenics (e.g., sodium cromoglycate, antazoline, methapyriline,chlorpheniramine); anti-inflammatories (e.g., hydrocortisone,hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,fluorocinolone, medrysone, prednisolone acetate, fluoromethalone,betamethasone, and non-steroidal agents such as indomethacin,diclofenac, flurbiprofen, ibuprofen and acetylsalicylic acid);mydriatics (e.g., atropine sulfate, cyclopentolate, homatropine,scopolamine, tropicamide, eucatropine, and hydroxyamphetamine);sympathomimetics such as epinephrine; immunological drugs such asvaccines and immune stimulants; beta adrenergic blockers such as timololmaleate, levobunclol HCl and betaxolol HCl; growth factors such asepidermal growth factor and fibronectin; carbonic anhydrase inhibitorssuch as dichlorphenamide, acetazolamide and methazolamide and otherdrugs such as prostaglandins, antiprostaglandins, and prostaglandinprecursors; angiogenesis inhibitors such as steroids, angiostatin,antiproliferative agents such as fluorouracil and mitomycin;anti-angiogenic factors; immunomodulatory agents; vectors for genetransfer (e.g, DNA plasmids, viral vectors); cytotoxic agents, andchemotherapy medications.

Examples of diagnostic agents include imaging agents, such as contrastagents. The reservoir contents also can be selected from catalysts(e.g., zeolites, enzymes), non-therapeutic reagents, precursors forcombinatorial chemistry, or combinations thereof, for example for use indiagnostic sensing and analytical biochemistry. The reservoir contentsalso could be non-biomedical molecules, such as fragrance molecules.

The reservoir contents also can include a secondary device, such as asensor and sensing component. In a particularly preferred embodiment,the reservoirs contain pressure sensors, for example to measureintraocular pressure. The reservoir contents may either be released fromor remain immobilized in the reservoir, depending on the particularapplication.

Types of sensors that can be contained within or provided near areservoir include biosensors, chemical sensors, physical sensors, oroptical sensors. Preferred sensors measure properties such as biologicalactivity, chemical activity, pH, temperature, pressure, opticalproperties, radioactivity, and electrical conductivity. These may bediscrete sensors (e.g., “doff-the-shelf” sensors) or sensors integratedinto the substrate. Biosensors typically include a recognition elementsuch as an enzyme or antibody. The transducer used to convert theinteraction between the analyte and recognition element into anelectronic signal may be, for example, electrochemical, optical,piezoelectric, or thermal in nature. Representative examples ofbiosensors constructed using microfabrication methods are described inU.S. Pat. No. 5,200,051, No. 5,466,575, No. 5,837,446, and No.5,466,575.

There are several different options for receiving and analyzing dataobtained with the secondary devices located in the microchip devices.First, the output signal from the device can be recorded and stored inwriteable computer memory chips Second, the output signal from thedevice can be directed to a microprocessor for immediate analysis andprocessing. Third, the signal can be sent to a remote location away fromthe microchip. For example, a microchip can be integrated with a radiotransmitter in order to transmit a signal (e.g., data) from themicrochip to a computer or other remote receiver source. The microchipcan also be controlled using the same transmission mechanism. Power canbe supplied to the microchip locally by a microbattery or remotely bywireless transmission. Ophthalmic lasers can be used to wirelesslytransmit power and data, as described in detail below.

Individual reservoirs may contain multiple types of chemicals, multipletypes of devices, or combinations of devices and chemicals. In variousembodiments, the microchip devices may include one or more drugs, one ormore sensors, or combinations thereof.

Interface with the Eye or Other Implantation Sites

The microchip devices described herein are useful at a variety of sitein which a single, larger, rigid microchip device may not be preferred.Examples of such sites include, but are not limited to, implantationsites in humans and other mammals. As used herein, “implantation” and“implanting” typically refer to securely positioning a microchip deviceonto a tissue surface. For example, the microchip devices describedherein can be attached to an outer surface of the eye or implantedwithin the eye using or adapting known medical and surgical techniques.

Alternatively, the device is designed to conform to another curvedtissue surface, such as the skin, mucosal tissue surfaces, blood vesselwalls (interior or exterior side), the stratum corneum or other skintissues, mucosal membranes, blood vessels, bone (e.g., the skull, thefemur), brain, and other organs tissue surfaces, such as the bladder.Such devices can be used for drug delivery and sensing applications. Theflexible devices also may serve to reposition the contacted tissue fortherapeutic purposes, such as to mechanically maintain the patency of atissue lumen, for example, while releasing anti-coagulants oranti-atherosclerotic agents. In the bladder, the flexible device couldbe used, for example, to deliver bacillus Calmette-Guérin (BCG) to theinterior surface for the treatment of superficial bladder cancer.

Power and Data Transmission

The active microchip devices require power to initiate release ofmolecules from the reservoirs or exposure of reservoir contents. Thereare two primary methods of supplying power to initiate release orexposure from active microchip devices. These include the use ofpre-charged power sources and the use of on-demand power sources.Pre-charged power sources (e.g., pre-charged micro-batteries) can beintegrated with the microchip and its associated electronics. Such apre-charged micro-battery can be, for example, a thin film batteryfabricated on the microchip itself, or it can exist as a separatecomponent that is connected to the microchip through interconnects andpackaging. In the case of pre-charged power sources, the power sourcemust store all the power required during the operating lifetime of themicrochip. If it cannot store all of the required power, then a newbattery at some point must replace the old battery during the life ofthe microchip.

On-demand power sources (e.g., wireless transmission and reception ofpower) do not require a power storage unit to be physically connected toor included with the microchip, because the necessary power can betransmitted to the microchip at any time. Unlike pre-charged powersources, microchip systems with the capability to receive power bywireless methods do not need to store all of the power required for theoperating life of the microchip. Instead, power can be applied to themicrochip on demand (i.e. when needed). However, microchips relying onon-demand power sources can include a “re-chargeable” power storage unit(i.e. capacitor, re-chargeable micro-battery), if it is desired to storesmall amounts of power on or near the microchip. The distinction is thatpre-charged power sources must contain all the required power or bereplaced, and on-demand power sources do not have to contain all therequired power because they can receive power or be re-charged at anytime. On-demand power by wireless transmission is known, and isdescribed for example in U.S. Pat. No. 6,047,214 to Mueller, et al.;U.S. Pat. No. 5,841,122 to Kirchhoff; and U.S. Pat. No. 5,807,397 toBarreras. The basic elements of a system for the wireless transmissionof power to a microchip for chemical release or selective exposure ofreservoir contents include a transmitter to deliver power by means ofelectromagnetic waves (i.e. radio frequency signal generator or RF),light (e.g., ophthalmic laser) or ultrasound, and a receiver. Additionalcomponents may include a means of power conversion such as a rectifier,a transducer, a power storage unit such as a battery or capacitor, andan electric potential/current controller (i.e.potentiostat/galvanostat).

Each of these units (except for the external energy transmission source)may be fabricated on the microchip (“on-chip” components) using MEMSfabrication techniques as described, for example, in Madou, Fundamentalof Microfabrication (CRC Press, 1997) or using standard microelectronicsprocessing techniques as described, for example, in Wolf & Tauber,Silicon Processing for the VLSI Era (Lattice Press, 1986). In addition,each of these units (except the external energy transmission source) mayexist as “off the shelf” microelectronic components that can beconnected to the microchips using hybrid electronic packaging ormulti-chip modules (MCMs). An active microchip with the capability ofreceiving power through wireless means also can be composed of acombination of “on-chip” components and “off the shelf” components.Methods for sending and receiving data using wireless technology arevery similar to those used for the wireless transmission of power.Therefore, the design and fabrication of such wireless power and datatransmission systems are known or can be made using no more than routineexperimentation by those skilled in the art.

OPHTHALMIC EMBODIMENTS

In one embodiment, the ophthalmic microchip device is in the form of anarray of small, rigid, drug-containing microchips that are attached to aflexible supporting layer so that the entire array can conform to theouter surface of the back of the eye. The microchips are connected toeach other by flexible electrical connections incorporated into thesupporting layer. In this embodiment, the array of microchips iscontrolled by a single microprocessor and power is supplied by a smallbattery. The array is attached to the back surface of the eye and isheld in place by several small sutures through the supporting layer andinto the outer tissue of the eye. The microprocessor is preprogrammed torelease drug from specific reservoirs by directing power from thebattery to specific reservoir caps through multiplexing circuitry. In aspecific embodiment, the caps are made of gold and they disintegrate inbiological solutions when electric potentials of approximately 1 volt(vs. SCE) are applied to them. Once the drug is released from areservoir, it is in contact with the surface of the eye and diffusesinto the eye. This process can be repeated numerous times with severaldifferent drugs being released from a single microchip or array ofmicrochips. The type and configuration of device components and thenumber of microchips in the array can be varied as needed for particularapplications.

This embodiment is illustrated in FIGS. 1A-C. FIGS. 1A and 11B show, inplan and cross-sectional views, respectively, an ophthalmic microchipdevice 50, which includes microchip device elements 54 attached toflexible supporting material 52. In this active-release embodiment, thedevice 50 also includes active electronics 56 (e.g., microprocessors,multiplexers, timers, etc.) and a microbattery 58. Each microchip deviceelement 54 includes substrate 60 containing a plurality of reservoirs62. The reservoirs can contain drugs or other reservoir contents asdescribed herein. FIG. 1C illustrates how the device 50 could beimplanted onto the surface of the eye. The cross-sectional view of theeye (wherein the surface of the eye is represented by a curved, dashedline) onto which device 50 is mounted with sutures 64. Other techniquesknown in the art also could be used to secure the device as appropriate.

Methods of Using the Devices

The microchip device elements can be used and operated generally asdescribed in No. 5,797,898, U.S. Pat. No. 6,123,861, PCT WO 01/64344,PCT WO 01/35928, and PCT WO 01/12157, and as described herein.

As described herein, reservoir activation can be conducted wirelessly.Generally, this refers to telemetry (i.e. the transmitting andreceiving) accomplished using a first coil to inductively coupleelectromagnetic energy to a matching/corresponding second coil. Themeans of doing this are well established, with various modulationschemes such as amplitude or frequency modulation used to transmit thedata on a carrier frequency. The choice of the carrier frequency andmodulation scheme will depend on the location of the device and thebandwidth required, among other factors. Other data telemetry means alsomay be used. Examples include optical communication, where the receiveris in the form of a photocell, photodiode, and/or phototransistor, andwhere the transmitter a light-emitting diode (LED) or laser.

Light Actuation of Microchip Devices

The power requirements for electrochemically actuated silicon microchipdevices with thin film gold reservoir caps are sufficiently small thatthis power can be supplied optically. An ophthalmic laser can be used toboth supply the power and communicate instructions to the device, as isdone in many wireless systems where the signal carrying power ismodulated to contain information to be communicated to the device.Alternatively, focused light from a non-laser source can be sufficientto operate the device.

In a preferred embodiment, focused light, such as from a laser source,is used to activate or actuate the reservoirs of microchip devicesfollowing implantation of the device. For example, lasers are usedroutinely in eye surgeries and other eye procedures for the treatment ofconditions such as diabetic retinopathy, retinal detachments, andage-related macular degeneration. Many of these procedures are simple,outpatient procedures carried out in an ophthalmologist's office. Themicrochip devices can be implanted into the eye and then activated usingsuch lasers to transmit power, data or both for powering and controllingthe device. An ophthalmologist can initiate drug release andcommunication with eye-implanted microchips by directing an ophthalmiclaser toward the appropriate portion of the microchip in (or on) thepatient's eye for those locations (i.e. implantation sites) where themicrochip device is readily accessible. Many ophthalmologists arealready skilled in the use of such lasers.

In a preferred embodiment the implanted wireless ocular delivery systemincludes the drug-containing microchip, controller, externalinterface(s), power conversion electronics, and actuation electronics.The external interface and power conversion electronics typicallyconsists of a photocell to receive the incident light (e.g., laser)energy, circuitry to generate the needed voltage(s), storage means suchas a capacitor or battery, and circuitry to decode informationtransmitted by modulating the laser input. The controller typically is amicroprocessor, memory, clock, though a dedicated integrated circuit maybe useful for some applications.

Electronics required to actuate electrochemical microchips includesmeans for controlling the electrode potential, such as apotentiostat/galvanostat, and a demultiplexer to direct the potential tothe desired reservoir(s). If desired, the system can provide feedback,for example, to confirm the successful delivery of a dose. Thisinformation can be transmitted back to the operator or to a computermonitoring system optically using a light-emitting diode (LED) or byother modes of wireless transmission (e.g., RF).

Wireless Reservoir Activation

Ophthalmic lasers also can be used to open the reservoirs of microchipdevices implanted inside the eye or attached to the outside of the eye.The physician can direct the laser to one or more reservoir caps,causing the cap material to disintegrate or become permeable, therebyreleasing the drugs or chemicals contained in the reservoir or exposingother reservoir contents (e.g., sensors) of the reservoir to thesurrounding environment. For example, the reservoir cap is made of a lowmelting temperature polymer and the reservoir is opened when the lasersoftens or melts the reservoir cap.

In one embodiment, a microchip device having polymeric reservoir caps isimplanted into the interior of the eye and held in place with sutures.The polymer caps do not dissolve or allow the drug to be released intothe eye without the application of an external stimulus. In thisembodiment, an ophthalmic laser is directed at one or more polymericreservoir caps when release is desired from the correspondingreservoirs. The ophthalmic laser creates a local increase in temperaturethat causes the polymeric reservoir cap to soften and melt. The druginside that reservoir then diffuses out of the reservoir and into theintraocular fluid. This implanted device can be used, for example, todeliver drug as needed over an extended period of time. For example, thepatient can visit the physician periodically, e.g., every two to fourweeks, and the physician uses an ophthalmic laser to open one reservoir(or several of them) of the implanted microchip device to release drugsinto the patient's eye.

In a similar embodiment, the physician uses the ophthalmic laser to opena reservoir that contains one or more sensors, which can be exposed bythe physician when desired. Representative sensors included pressuresensors, chemical sensors, and immunological sensors. A chemical sensor,such as an oxygen electrode, is one example of a useful sensor. Anotherexample is a pressure sensor, which can be used to help monitor theprogression of some eye diseases, such as glaucoma, by measuring andrecording pressure changes in the eye. The pressure sensing function canbe related to the release of drug from another reservoir, so that, forexample, upon detection of an abnormally high intraocular pressure, themicrochip device signals the release of a pressure reducing drug fromanother microchip reservoir, which can be in the same device or inseparately fabricated device that is in communication with the pressuresensing microchip device.

An implantable wireless ocular delivery system would typically include(1) the microchip device (containing one or more drugs and/or sensors)with its local controller, external interfaces, power conversionelectronics, and actuation electronics; and (2) the focused lightsource. The external interface and power conversion electronicstypically would include a photocell to receive the incident lightenergy, circuitry to generate the needed voltage, storage means such asa capacitor or battery, and circuitry to decode information transmittedby modulating the laser input. The controller typically would be amicroprocessor with associated support circuitry such as a memory and aclock, although a dedicated integrated circuit may work for someembodiments. Electronics required to actuate electrochemical microchipstypically would include means for controlling the electrode potential,such as a potentiostat or galvanostat, and a demultiplexer to direct thepotential to the desired reservoir. If desired, the system would providefeedback, for example, to confirm the successful delivery of a dose.This information could be transmitted back to the operator or to acomputer monitoring system, either optically by using a light-emittingdiode (LED) or by other modes of wireless transmission, such as E.

FIG. 2A illustrates one possible configuration of the microchip deviceconfiguration, wherein microchip device 10 includes an array ofreservoirs 12 containing drug to be released or sensor to be exposed,power conversion, actuation electronics and local controller area 14,photocell 16, LED or wireless telemetry transmitter 18.

An ophthalmologist could initiate drug release and communication witheye-implanted microchip device by directing an ophthalmic laser towardthe appropriate portion of the implanted microchip in the patient's eye.See FIG. 2B, which illustrates an eye 20 with optic nerve 21, whereinmicrochip device 28 is implanted at the back of the interior of the eye.An ophthalmic laser 30 directs power and data via laser light 32 throughcornea 22, lens 24, and vitreous humor 26, to power and communicate withthe implanted microchip device 28. Many ophthalmologists are alreadyskilled in the use of such lasers, so these procedures could be readilyperformed.

Applications of the Ophthalmic Microchip Devices

The microchip devices and methods of use can be used for a variety oftherapeutic, prophylactic, and diagnostic ophthalmic applications, aswell as other (non-ophthalmic) medical implant application.

In a preferred embodiment, the devices are used in the treatment ofretinal or choroidal diseases, such as macular degeneration, glaucoma,diabetic retinopathy, retinitis pigmentosa, retinal vein occlusions,sickle cell retinopathy, choroidal neovascularization, retinalneovascularization, retinal edema or ischemia.

In some applications, the devices are used in the control ofinappropriate proliferation of cells on or within the eye. The specifictype and location of the cells depends upon the particular disease ordisorder. Examples of types of inappropriate cell proliferation includecancerous malignancies, wherein the cell is a cancer cell, scarring,wherein the cell is a normal fibroblast, and diseases wherein theproliferating cell is an epithelial cell, such as a lens epithelialcell, which can impair vision. One specific application is theinhibition of wound healing at the site of implantation of a filteringbleb or fistula to create a drainage channel for aqueous humor outflowto lower elevated intraocular pressure, which is associated withglaucoma.

Other Applications of the Microchip Device Arrays

The devices described herein have a wide variety of both medical andnon-medical uses. For example, other medical applications for themicrochip devices include drug delivery and sensing at sites such as thewall (interior or exterior side) of a blood vessel and on or withinother organs such as the bladder. Other tissue surfaces (i.e.implantation sites) include skin (e.g., the stratum corneum, forexample, where the microchip device could be used for transdermal drugdelivery) and mucosal tissue surfaces (e.g., for vaginal or buccal drugdelivery), blood vessel walls (interior or exterior side), and otherorgans, such as the bladder.

Representative non-medical uses include industrial diagnostics, chemicalresearch, consumer products (e.g., fragrance release), etc.

Modifications and variations of the methods and devices described hereinwill be obvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

1. A method of selectively opening a containment reservoir, comprising:providing a device which comprises a substrate in which at least onereservoir is located and covered by a first reservoir cap; and directinglaser light to the reservoir cap to cause the reservoir cap todisintegrate or become permeable.
 2. The method of claim 1, wherein thereservoir cap comprises a polymer.
 3. The method of claim 1, wherein thedevice is an implantable medical device.
 4. The method of claim 1,wherein the reservoir contains a drug.
 5. The method of claim 4, whereinthe drug comprises a therapeutic or prophylactic agent which is selectedfrom the group consisting of anti-microbials, anti-allergenics,anti-inflammatories, vaccines, growth factors, carbonic anhydraseinhibitors, angiogenesis inhibitors, angiostatin, antiproliferativeagents, anti-angiogenic factors, immunomodulatory agents, gene transfervectors, cytotoxic agents, and chemotherapy medications.
 6. The methodof claim 1, wherein the reservoir contains a biosensor.
 7. A method ofselectively opening a containment reservoir, comprising: providing adevice which comprises (i) a substrate in which a plurality ofreservoirs are located, and (ii) a plurality of reservoir caps, each ofsaid reservoir caps covering one of the reservoirs; at a first time,directing laser light to a first reservoir cap to cause the firstreservoir cap to disintegrate or become permeable; and at a second,later time, directing laser light to a second reservoir cap to cause thesecond reservoir cap to disintegrate or become permeable.
 8. A kit ofparts, comprising; an implantable medical device which comprises asubstrate in which at least one reservoir is located and covered by areservoir cap; and a laser for directing laser light to the reservoircap to cause the reservoir cap to disintegrate or become permeable. 9.The kit of claim 8, wherein the reservoir contains a drug releasablefollowing disintegration or permeabilization of the reservoir cap by thelaser light.
 10. The kit of claim 8, wherein the substrate comprises aflexible polymeric material or wherein the substrate is attached to aflexible supporting layer.
 11. The kit of claim 8, wherein the laser isan ophthalmic laser.